One Night in San Diego:
Tragedy of Alcohol Abuse Drives TSRI Researcher's Work

By Jason Socrates Bardi


That which hath made them drunk hath made me bold;
What hath quench'd them hath given me fire.

——Macbeth Act II, scene 2

An affluent man in his 60s, drunk, pushes past his pleading wife, gets in his late model Cadillac, guns it out of the gas station where the two have been fighting over the keys, and drives the wrong way up the freeway off ramp, running head-on into a car, killing the driver, and injuring himself.

At around the same time, a prominent member of a San Diego community, blind-drunk, crashes his family minivan into several parked cars along his street. Nobody is hurt, but after the story breaks, he will be forced to resign.

A few hours later, some teenagers are drinking and blasting around in their old Ford pickup truck. A momentary lapse or some loose gravel and they plunge off the road and down a canyon. Luckily, they are not hurt, but they have to wait until morning before an emergency crew can climb down and haul them out.

According to The Scripps Research Institute (TSRI) Neuropharmacology Professor George F. Koob, these three stories—based on actual events that transpired on a single night in San Diego last year—highlight how problems related to alcohol cut across nearly all social, financial, and age-related strata.

Koob has been studying the neurobiology of alcohol and alcoholism for several years, and he has developed models of normal and excessive drinking to study the neurophysiological correlates of alcohol consumption. His studies start with the brain and the neurobiology of alcohol in the brain—some of which we understand, and some of which is only now coming to light.

"Despite many years of independent study of the biochemistry, physiology, systems, and processes hypothesized to be involved in alcoholism, the mechanisms are still unclear," says Koob.

An Enigma in a Bottle

Of all the legal and illegal drugs, alcohol is both one of the most readily available and one of the most toxic. It holds an enigmatic place in American society.

On the one hand, alcohol is regularly or occasionally consumed in various forms by nearly two thirds of all American adults, and there are few who have not consumed alcohol on occasion. According to United States Centers for Disease Control and Prevention statistics, four fifths of the U.S. adult population have been regular or occasional drinkers at one time.

Alcohol is the great "social lubricant" that humans have imbibed for at least 7,000 years (the age of the oldest known wine jugs ever found by archeologists). The Egyptians loved wine so much that they imported grapes. The Greeks celebrated the joys of inebriation through their god of wine, Dionysus. The Romans called the same god Bacchus.

On the other hand, alcohol extracts a heavy toll on society.

Drunk driving is a major scourge in the United States—about a third of the approximately 40,000 traffic fatalities every year involve drunk drivers. Thousands more die each year from accidental or deliberate alcohol poisoning, and from alcohol-related degenerative conditions like gastritis, cardiomyopathy, and liver disease. In 1999, according to the Centers for Disease Control and Prevention (CDC), a total of 19,171 persons in the United States died from such causes. And fetal alcohol syndrome, caused by alcohol consumption by pregnant women, is the leading cause of mental retardation in the United States. The CDC estimates that as high as one out of every thousand babies born in the United States each year suffers from fetal alcohol syndrome, and they report that the heath costs related to these children was $1.9 billion in 1992—the last year for which they report such statistics.

One of the most terrible costs of excessive drinking is, of course, alcoholism—the chronic compulsive use of and loss of control over alcohol intake. For reasons that are not entirely clear, some portion of the people who drink suffer from some form of alcoholism.

In addition to its enormous toll on families and society at large, alcoholism is devastating to an individual's health because of the damage that excessive amounts of alcohol cause to the system over time. Whether it is the liver or the heart or some other organ, says Koob, "Ultimately, alcoholism gets you as some part of your body goes."

The direct and indirect public health costs of alcoholism are estimated to be in the hundreds of billions of dollars yearly. Currently, there is no cure for alcoholism, and the neurobiology of the disease is not completely understood.

"Why does 10 to 15 percent of the population become alcoholic and the rest of the population does not?" asks Koob. "For instance, we know that the children of alcoholics are four to five times more likely to become alcoholics themselves, but we do not know what the neurological basis for this trait is."

A Consortium Seeks Answers

Last year, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) funded a multi-year consortium headed by Koob to identify the molecular basis of alcoholism. The aim of the Integrative Neuroscience Initiative on Alcoholism consortium grant is to address the basic science of alcoholism and to establish a platform upon which future treatments can be built.

The grant supports the combination of physiological, molecular, and cellular models to derive the genetic and environmental factors that form the basis for individual differences in developing excessive drinking. A large portion of the funding is dedicated to setting up shared facilities to centralize and enhance some of the tasks common to the researchers with independently funded research projects.

"The goal is to figure out what makes people vulnerable to excessive drinking," says Koob. "What is the genetic loading and how does that interact with environmental determinants?"

A neuroinformatics group, for instance, will make use of the newly solved human and the soon-to-be-completed mouse genomes to interpret "gene chip" screens needed to identify the genes involved. Certain gene clusters are regulated by alcohol and may be differentially regulated during the development of excessive drinking.

Another group will establish animal models of alcoholism that will be used to study these genes in action.

The Effects of Alcohol on the Brain

Scientists used to think of alcohol as a membrane disruptor with a generalized effect all over the brain, as the small molecule can freely diffuse across the blood–brain barrier. They now know that there are particular cells in the brain that alcohol targets by binding certain hydrophobic pockets on their surface receptors. The gamma-aminobutyric acid (GABA) receptor is one of these. "Alcohol is an indirect GABA agonist," says Koob.

GABA is the major inhibitory neurotransmitter in the brain, and GABA-like drugs are used to suppress spasms. Alcohol is believed to mimic GABA's effect in the brain, binding to GABA receptors and inhibiting neuronal signaling.

Alcohol also inhibits the major excitatory neurotransmitter, glutamate, particularly at the N-methyl-d-aspartate (NMDA) glutamate receptor. And it releases other inhibitors, such as dopamine and serotonin. Consumption of even small amounts of alcohol increases the amount of dopamine in the nucleus accumbens area of the brain—one of the so-called "reward centers." However, it is most likely that the GABA and glutamate receptors in some of the reward centers of the basal forebrain—particularly the nucleus accumbens and the amygdala—create a system of positive reinforcement. In fact, multiple neurotransmitters in various parts of the brain combine to make the consumption of small doses of alcohol enjoyable.

"Alcohol tends to activate the whole reward system," says Koob, who is particularly interested in the effects of alcohol in the amygdala.

The neurochemical effects of alcohol cause a range of short-term effects—from a mild buzz to slow reaction times, which make drunk driving so dangerous. In the long term, these effects are also the basis for two of the defining characteristics of addiction: tolerance and dependence.

Tolerance and Overdrinking

Tolerance to alcohol is one aspect of alcoholism that leads to overdrinking. Tolerance can be acute, in one bout of drinking, or long-term, requiring an ever-larger dose to get the same effect over time.

The effect of acute tolerance is a common experience for anyone who has had more than a few drinks. Initially, the first drink has a relaxing effect, but as a person continues drinking, it takes more and more alcohol to produce the same effect. Some people have more acute tolerance than others—probably due to genetic factors. "These are the people who can drink anybody else under the table," says Koob. He adds that these people may also be at increased risk of developing dependence on alcohol because of their increased tolerance.

Dependence to alcohol is linked to the interaction of alcohol with the brain's stress system, which alcohol activates. The major component of the brain stress system is the corticotropin-releasing factor (CRF) in the amygdala and related areas, which activates sympathetic and behavioral responses to stress. A normal stress response sees CRF recruiting other parts of the brain to help adapt the mind and body to deal with the physical and mental "stressors" that challenge it. Alcohol interacts in such a way as to acutely reduce CRF levels in the brain; chronic alcoholism does the opposite.

Koob hypothesizes that there also may be individuals who are at increased risk of becoming alcoholics because their genetic makeup causes them to have higher CRF levels than normal.

"They may be drinking to feel normal—they may drink to tame a hyperactive CRF stress system in the brain," he says.

Unfortunately, CRF and the stress system adjust to the alcohol. CRF is hypothesized to persist at artificially high levels in the brain while reward neurotransmitters are compromised. In alcoholism, the effect is even more pronounced and results in an equilibration of neurotransmitter levels at artificial, "allostatic" set-points—an equilibration driven by chronic alcohol ingestion. In the absence of alcohol, the alcoholic feels ill because his or her body cannot easily reverse these artificial levels (for example, high CRF and low reward neurotransmission).

This ill feeling may contribute to the tendency of the alcoholic to overdrink—a danger because of the toxic effect on the brain and body of subjecting oneself to so much alcohol.

Sadly, the brain often does not perceive the consequences of the short-term relief that the alcohol brings. When a person overdrinks, there is depleted GABA function in the brain and also, possibly, a hyper-excitable glutamate system. Alcoholics feel good while they are boozing. However, this short-term relief makes the whole system worse off.

Understanding Stress is Important for Treatment

Not only is stress part of the spiral disregulation of motivational processes involved in the development of alcoholism, but stress is one of the most common states associated with relapse. Relapse also occurs as a consequence of behavioral patterns, such as walking by the old saloon or hanging around with familiar drinking buddies. "Before you know it, you're back into it," says Koob.

Alcoholics drink when they're happy, alcoholics drink when they're sad, and they drink when they are stressed. "Any excuse to drink," he says.

In the treatment of alcoholism, a person is especially vulnerable to relapse for a year to 18 months after cessation of drinking, a period Koob refers to as "protracted abstinence." One of Koob's research interests is in protracted abstinence and the residual changes in the brain that take place during it.

These are very important studies because behavior plays such a large role in relapse, and behavioral therapy is a prominent part of the recovery process. Most alcoholism treatment programs involve some form of behavioral therapy—whether through professional counseling or a group like Alcoholics Anonymous. The goal of much of Koob's work is to someday help individuals who have become addicted to alcohol.

"It's very possible that we are going to find brain areas that code for certain proteins responsible for the individual differences that make 15 percent of the population vulnerable to alcoholism and/or that protect 85 percent," says Koob.

"Once we know the circuits and the basis for alcoholism, we can develop new targeted treatments."



Horizontal section of a rat brain depicting the principal structures of the extended amygdala. These include the central nucleus of the amygdala, the shell part of the nucleus accumbens, and the bed nucleus of the stria terminalis. The drugs listed below each structure refer to potential sites of action of drug reinforcement during the addiction cycle, either positive or negative.



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Professor George F. Koob studies the neurobiology of alcohol and alcoholism. Photo by Kevin Fung.